title: Mechanisms of STAT3 activation in the liver of FXR knockout mice.
abstract: Farnesoid X receptor (FXR, Nr1h4) is a ligand-activated transcription factor belonging to the nuclear receptor superfamily. FXR is essential in maintaining bile acid (BA) homeostasis, and FXR(-/-) mice develop cholestasis, inflammation, and spontaneous liver tumors. The signal transducer and activator of transcription 3 (STAT3) is well known to regulate liver growth, and STAT3 is feedback inhibited by its target gene, the suppressor of cytokine signaling 3 (SOCS3). Strong activation of STAT3 was detected in FXR(-/-) mouse livers. However, the mechanism of STAT3 activation with FXR deficiency remains elusive. Wild-type (WT) and FXR(-/-) mice were used to detect STAT3 pathway activation in the liver. In vivo BA feeding or deprivation was used to determine the role of BAs in STAT3 activation, and in vitro molecular approaches were used to determine the direct transcriptional regulation of SOCS3 by FXR. STAT3 was activated in FXR(-/-) but not WT mice. BA feeding increased, but deprivation by cholestyramine reduced, serum inflammatory markers and STAT3 activation. Furthermore, the Socs3 gene was determined as a direct FXR target gene. The elevated BAs and inflammation, along with reduced SOCS3, collectively contribute to the activation of the STAT3 signaling pathway in the liver of FXR(-/-) mice. This study suggests that the constitutive activation of STAT3 may be a mechanism of liver carcinogenesis in FXR(-/-) mice.
authors.affiliation: Dept. of Pharmacology and Toxicology, School of Pharmacy, Rutgers Univ., Piscataway, NJ 08854. guo@eohsi.rutgers.edu.
authors.forename: Guodong
authors.initials: G
authors.lastname: Li
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhu
authors.forename: Ossama
authors.initials: O
authors.lastname: Tawfik
authors.forename: Bo
authors.initials: B
authors.lastname: Kong
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Williams
authors.forename: Le
authors.initials: L
authors.lastname: Zhan
authors.forename: Karen M
authors.initials: KM
authors.lastname: Kassel
authors.forename: James P
authors.initials: JP
authors.lastname: Luyendyk
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.forename: Grace L
authors.initials: GL
authors.lastname: Guo
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000172:deficiency / Q000378:metabolism / Q000494:pharmacology; D002792:Cholestyramine Resin / Q000494:pharmacology; D016207:Cytokines / Q000097:blood / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D001647:Bile Acids and Salts; D002792:Cholestyramine Resin; D016207:Cytokines; D018160:Receptors, Cytoplasmic and Nuclear; D050796:STAT3 Transcription Factor; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D000099150:Receptor, Farnesoid X-Activated; C491411:Socs3 protein, mouse; C494087:Stat3 protein, mouse
keywords: bile acids; cancer; farnesoid X receptor; signal transducer and activator of transcription 3; suppressor of cytokine signaling 3